Isoliquiritigenin (ISL) is a bioactive chalcone obtained from licorice, the ground root of Glycyrrhiza glabra. We previously identified ISL as a late-phase autophagy inhibitor in pancreatic cancer treatment. This study aimed to further explore the involvement of selective autophagy and tumor immunity in its antineoplastic action. Network pharmacology revealed that ISL would downregulate biological processes associated with pancreatic ductal adenocarcinoma (PDAC) including cell migration, extracellular matrix organization and wound healing. Our experimental findings further confirmed ISL's role in inhibiting the epithelial-mesenchymal transition, a key mechanism involved in these processes. ISL also increased the production of reactive oxygen species in both PANC-1 and MIA PaCa-2 PDAC cells, which was intensified through inhibition of autophagy. Furthermore, ISL downregulated glutathione peroxidase 4 (GPX4) and the system Xc- counter-transporter of cystine SLC3A2, while increasing the expression of nuclear receptor coactivator 4 (NCOA4) and decreasing that of ferritin heavy chain 1 (FTH1), thereby promoting ferritinophagy-activated ferroptosis. Alternatively, ISL could induce mitophagy by facilitating mitochondrial dynamics toward fusion through an increase in Parkin and MFN1 gene expression. ISL also modulated the robust transcriptional stress response associated with autophagy and ferroptosis through regulation of CREB1 and VMP1. In the tumor microenvironment, ISL decreased the number of myeloid-derived suppressor cells (MDSCs) while increasing the number of CD4[Formula: see text] and CD8[Formula: see text] T cells in the spleen, tumor tissues and blood of Pan02-xenografted mice. ISL also impaired M2 polarization of macrophages in tumor tissues. The inhibitory effects of ISL could be attenuated by interferon-[Formula: see text] through STAT1 signaling. These results demonstrate that ISL regulates selective autophagy-mediated ferroptosis associated with modulation of the tumor microenvironment when treating pancreatic cancer.
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent inflammation and progressive joint damage. This study investigated the role of microRNA-223 (miR-223) in RA and evaluated the therapeutic effects of triptolide (Tri), a diterpenoid epoxide derived from the traditional Chinese medicinal herb Tripterygium wilfordii. A collagen-induced arthritis (CIA) mouse model was used to assess the effects of Tri and methotrexate (MTX). Micro-computed tomography, histological staining, enzyme-linked immunosorbent assay, flow cytometry, RT-qPCR, and western blot analysis were used to evaluate joint damage, inflammation, cytokine profiles, miR-223 expression, and the function of CREBZF, a downstream target of miR-223. CIA mice exhibited marked joint inflammation, swelling, bone erosion, and inflammatory cell infiltration, increased pro-inflammatory cytokine levels, and elevated miR-223 expression. Tri and MTX ameliorated these abnormalities and protected against bone erosion and inflammation. Tri suppressed the disease-associated elevation of miR-223, attenuated pathological fibroblast-like synoviocyte (RA-FLS) phenotypes, and shifted cytokine profiles toward an anti-inflammatory state. Dual-luciferase reporter and AGO2-RIP-qPCR assays supported direct regulation of CREBZF by miR-223. Tri restored CREBZF expression and inhibited NF-κ B signaling, thereby reducing RA-FLS proliferation and promoting apoptosis. These findings indicate that Tri ameliorates RA, at least partly, through the miR-223/CREBZF axis and identify this pathway as a potential therapeutic target.
Alzheimer's disease (AD), a progressive neurodegenerative disease with a rising global prevalence, is characterized by amyloid-β (Aβ) aggregation, tau hyperphosphorylation, inflammation, oxidative damage, and neuronal apoptosis. Studies have increasingly recognized epigenetic modifications as key regulators in the development of AD. Epigenetic modifications, particularly histone acetylation, are increasingly recognized as critical regulators of cell survival and AD pathogenesis. Although artemisinin (ART) exhibits potent anti-oxidative, anti-inflammatory, and neuroprotective properties, its impact on histone acetylation in AD remains uncharacterized. This study investigated whether ART regulates histone acetylation to confer neuroprotection and rescue behavioral deficits in Alzheimer's disease models. Using SH-SY5Y cells, primary neurons, and 3xTg-AD mice, we found that ART restores histone acetylation homeostasis by enhancing histone H4 acetylation. Mechanistically, this effect is driven by the activation of the CaMK IV/PKA-CREB signaling cascade. Treatment with ART reduced ROS, improved mitochondrial function, decreased Aβ1-42 deposition, and suppressed neuronal apoptosis. However, these beneficial effects were abolished by PKA or CaMK IV inhibitors. Consequently, ART treatment significantly reduced reactive oxygen species (ROS) generation, restored mitochondrial function, decreased Aβ1-42 deposition, suppressed neuronal apoptosis, and alleviated AD-like neuropathology and cognitive deficits. Crucially, the neuroprotective and epigenetic benefits of ART were entirely abolished by pharmacological inhibitors of PKA or CaMK IV. This study is the first to demonstrate that artemisinin ameliorates AD pathology and behavioral impairments via the CaMK IV/PKA-CREB-Ace-H4 axis, establishing ART as a promising therapeutic candidate for epigenetic intervention in AD.
Berberine (BBR), the core alkaloid of the traditional Chinese medicine Coptis chinensis (Huanglian), exhibits a notable pharmacological paradox: it possesses an oral bioavailability of less than 1% yet exerts broad therapeutic effects across the full spectrum of liver diseases, from metabolic dysfunction-associated steatotic liver disease (MASLD) through fibrosis to hepatic malignancies. This review constructs an integrated mechanistic framework to interpret BBR's holistic pharmacological characteristics, which distinguish it from conventional single-target drugs. In MASLD, BBR engages a convergent AMPK-SIRT-Nrf2 network to ameliorate insulin resistance, lipid dysregulation, oxidative stress, and hepatic inflammation. Combined with the complementary actions of its bioactive metabolites, it achieves parent-metabolite coordinated efficacy that embodies the holistic principle of traditional Chinese medicine. In liver fibrosis, BBR may block hepatic stellate cell activation via the TGF-β1/Smad3 pathway and eliminate activated HSCs through multiple programmed cell death pathways, particularly ferroptosis, which may overcome apoptosis resistance. In hepatic malignancies, BBR suppresses tumor progression, metastasis, and chemoresistance via apoptotic, ferroptotic, and immunomodulatory mechanisms. Current clinical evidence validates its metabolic benefits in MASLD, whereas clinical data regarding fibrosis and hepatic malignancies remain insufficient. Improving its poor bioavailability through structural modification and nanocarrier delivery is critical for clinical translation. This review provides a modern pharmacological rationale for the clinical application of Coptis chinensis-based formulas against progressive liver diseases.
Triple-negative breast cancer (TNBC), a highly aggressive subtype of breast cancer characterized by poor prognosis and limited therapeutic options, remains a major clinical challenge. Bufalin, a principal bioactive component of Venenum Bufonis, exhibits potent anticancer activity against breast cancer. Nevertheless, the precise molecular mechanism by which bufalin triggers ferroptosis in TNBC cells remains poorly elucidated. In the present study, both in vitro and in vivo investigations were performed. Cellular ferroptosis was comprehensively evaluated by detecting intracellular Fe[Formula: see text], ROS, MDA, and reduced GSH levels, together with ultrastructural observation under transmission electron microscopy. Transcriptome sequencing combined with bioinformatic analysis was applied to screen the core regulatory mechanism of bufalin-induced ferroptosis in TNBC, and subsequent molecular biological experiments were conducted for further validation. The results demonstrated that bufalin significantly suppressed the proliferation and migration of TNBC cells. Bufalin treatment markedly increased Fe[Formula: see text], ROS, and MDA levels, depleted intracellular GSH, and induced mitochondrial shrinkage and cristae damage. Transcriptome analysis identified the NRF2/HO-1/GPX4 signaling axis as the central pathway mediating the pharmacological effect of bufalin. Mechanistically, bufalin downregulated the expression of NRF2, HO-1, SLC7A11, and GPX4, whereas it upregulated KEAP1 expression. In vivo studies verified that bufalin effectively inhibited tumor growth with no obvious systemic toxicity. Moreover, bufalin decreased the expression of GPX4 and Ki-67, increased the number of TUNEL-positive cells, and blocked the activation of the NRF2/HO-1/GPX4 pathway in tumor tissues. In conclusion, bufalin induces ferroptosis in TNBC by inhibiting the NRF2/HO-1/GPX4 signaling pathway, thereby exerting antitumor effects. These findings indicate that bufalin serves as a promising therapeutic agent for TNBC treatment.
Panax notoginseng saponins (PNS), the chief saponin components of the traditional Chinese medicine Panax notoginseng, are known to ameliorate the outcomes of ischemic stroke (IS), primarily by mitigating inflammatory responses, enhancing microcirculation, and modulating oxidative stress. Damage to brain microvascular endothelial cells (BMECs) and BMECs' ferroptosis are critical steps in cerebral ischemia-reperfusion injury (CIRI), a process in which neutrophil extracellular traps (NETs) have been shown to induce BMECs injury, thereby aggravating CIRI. We aimed to investigate the regulatory effects of PNS on NETs and BMECs' ferroptosis following CIRI and evaluate its therapeutic efficacy in brain injury intervention. In this study, Sprague-Dawley rats were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R), and the BMECs were exposed to oxygen-glucose deprivation/reoxygenation (OGD/R). These models were pretreated with PNS or the NETs-degrading agent DNase I, and the ensuing changes in key proteins, NETs-related markers, inflammatory factors, and ferroptosis-related indicators were assessed using Western Blotting or specific assay kits. Finally, neurological injury was assessed by neurological function scores and triphenyl tetrazolium chloride staining, while cell viability was evaluated using the Cell Counting Kit-8 (CCK-8) assay. In the rat models, PNS and DNase I markedly reduced the levels of key NETs biomarkers, related inflammatory factors, as well as MCAO/R-triggered ferroptosis, thereby mitigating brain injury. PNS treatment effectively suppressed NETs-induced ferroptosis in BMECs in vitro, thereby alleviating cell injury. This study demonstrated that PNS alleviates CIRI by inhibiting NETs and BMECs' ferroptosis. Mechanistically, PNS suppresses NETs, thereby suppressing ferroptosis. Collectively, these findings support a pharmacological rationale underlying the clinical treatment of IS.
Inflammation is a pathological process central to many chronic diseases. Conventional anti-inflammatories, including NSAIDs and corticosteroids, are limited by adverse effects and suboptimal efficacy with long-term use. Ginsenosides from Panax ginseng have emerged as promising multi-target candidates with favorable safety profiles. This review systematically summarizes recent advances in research on the anti-inflammatory pharmacological effects and molecular mechanisms of ginsenosides, with particular emphasis on Rg1, Rb1, Rd, Re, and Rg3. Recent literature was collected and analyzed, and network pharmacology and bioinformatics approaches were employed to predict therapeutic targets and regulatory networks. Core anti-inflammatory mechanisms include suppression of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) and NF-κB signaling; modulation of TLR4/NF-κB and NLRP3 inflammasome activity; regulation of MAPK (ERK, JNK, and p38) phosphorylation; activation of Nrf2/HO-1 and Hippo-YAP/TAZ pathways; inhibition of COX-2 and iNOS expression; regulation of macrophage polarization; and modulation of membrane permeability and ion exchange. This study elucidates the association between ginsenosides and various inflammatory diseases, systematically consolidating their diverse molecular mechanisms underlying their treatment of typical inflammatory conditions. By integrating modern techniques such as network pharmacology and molecular docking, this review deepens our understanding of the efficacy of ginsenosides in the management of inflammatory diseases. It provides critical insights for further exploration of ginsenosides' pharmacological actions, the development of novel anti-inflammatory drugs, and the interpretation of the modern scientific basis underlying TCM concepts such as ginseng's "restorative and stabilizing" properties.
Myocardial infarction (MI) necessitates the promotion of angiogenesis to improve prognosis. Panax quinquefolius saponins (PQS), bioactive constituents of a medicinal and edible homologous plant, are known for their cardiovascular benefits, but their epigenetic mechanisms in post-MI angiogenesis remain unclear. In this study, PQS was obtained through a water extraction method followed by stepwise enrichment via ethanol elution. Surgical ligation of the left anterior descending (LAD) coronary artery was performed to establish an MI model in male C57BL/6 mice. The therapeutic effects on MI in each group were assessed through histopathological staining and echocardiography. The therapeutic effects of PQS on hypoxic human umbilical vein endothelial cells (HUVECs) were evaluated using tube formation assays, scratch assays, CD31 immunofluorescence, and Western blot (WB). Network pharmacology analysis, Bisulfite Sequencing PCR (BSP) detection, PCR, and WB were utilized to examine the influence of DNMT3b on Notch1 methylation. Cellular Thermal Shift Assay (CETSA) and Co-Immunoprecipitation (Co-IP) assays were employed to ascertain the binding interaction and stability between PQS and DNMT3b. Here, we demonstrate that PQS directly binds DNMT3b, thereby reversing aberrant DNA methylation at the Notch1 promoter and activating the Notch1/ubiquitin-specific protease 5 (USP5)/signal transducer and activator of transcription 3 (STAT3) signaling axis, thereby enhancing endothelial cell migration, tube formation, and angiogenesis in MI models. Ginsenoside Rc, ginsenoside Rh4, and vinaginsenoside R1 were identified as the key active components with the strongest DNMT3b binding affinity and angiogenic activity, with ginsenoside Rc demonstrating the most significant therapeutic effects. These findings reveal a novel epigenetic mechanism and confirm that PQS, particularly ginsenoside Rc, is a highly promising bioactive compound for promoting angiogenesis following MI.
Ginsenoside Rg2 (G-Rg2) is a key protopanaxatriol-type saponin from Panax ginseng. Increasing evidence has shown that G-Rg2 exerts pharmacological effects such as neuroprotection, immune regulation, anti-inflammation and inhibition of tumor proliferation by reducing inflammatory response, blocking apoptotic cascade and regulating autophagic flow. In terms of mechanism of action, the diverse biological effects of G-Rg2 result from its background-dependent regulation of key intracellular signaling pathways such as AMPK, MAPK, NF-κB and PI3K-AKT-mTOR, which are interconnected to form a complex regulatory network. This plasticity in pathway regulation confers bidirectional pharmacological properties of G-Rg2, which induces apoptosis through inhibition of the PI3K-AKT-mTOR pathway in MCF-7 breast cancer cells, whereas it activates the same pathway to promote cell survival in cardiomyocytes and neurons under ischemic conditions. Metabolomics and multiomics studies in animal models suggest that G-Rg2 regulates metabolic networks and multiple signaling pathways simultaneously in a complex disease environment, suggesting that G-Rg2 is most likely a network-level regulatory mode rather than a linear single-target action. The poor oral bioavailability, rapid systemic clearance, stereochemical complexity due to the 20(R)/20(S) isomers, and insufficient long-term safety data of G-Rg2 have hindered its translation into clinical trials. Based on existing mechanism-related research on G-Rg2, this review proposes a network-based regulatory framework and offers specific suggestions to enhance the bioavailability and targeting of G-Rg2, providing actionable directions for its clinical translation.
Phytoestrogens derived from natural products have emerged as potential alternatives to hormone replacement therapy (HRT) for alleviating menopausal symptoms with reduced adverse effects. However, the therapeutic potential and mechanistic basis of flaxseed-derived lignan secoisolariciresinol diglucoside polymer (SDGP) remain largely unexplored. This study aimed to investigate the synergistic effects of SDGP and a linusorb mixture (LOMIX) on menopausal symptoms and to elucidate their underlying molecular mechanisms. Estrogen receptor (ER) activation was evaluated using ERE-luciferase reporter assays and Western blot analysis in MCF-7 cells. Anti-osteoclastogenic effects were assessed in RANKL-induced RAW264.7 cells. An ovariectomized (OVX) rat model was used to examine in vivo efficacy on reproductive tissues and bone metabolism. Co-treatment with SDGP and LOMIX synergistically enhanced ERα/ERβ phosphorylation and Akt activation, leading to increased transcription of ER target genes. The combination also suppressed osteoclast differentiation by inhibiting NF-κB and MAPK signaling pathways, including c-Fos and NFATc1. In OVX rats, oral administration of the mixture restored vaginal cornification and uterine morphology, and significantly improved trabecular bone structure and bone mineral density. Notably, these effects were achieved without significant alterations in circulating estrogen, FSH, or LH levels. The combination of SDGP and LOMIX alleviates menopausal symptoms through non-hormonal activation of ER signaling and inhibition of osteoclastogenesis. These findings suggest a promising phytotherapeutic strategy for managing postmenopausal disorders with reduced risk of hormone-related side effects.
Acetaminophen (APAP) overdose is a leading cause of acute liver injury (ALI), yet effective therapeutic options remain limited. Although notoginsenoside R1 (NGR1) is a major bioactive saponin isolated from Panax notoginseng with established anti-inflammatory and anti-oxidant properties, its hepatoprotective potential and underlying mechanisms in APAP-induced liver injury (AILI) have not been systematically investigated. In this study, we established an AILI mouse model and evaluated the protective effects of NGR1 through biochemical assays, histopathology, Western blotting, and immunofluorescence, complemented by integrative transcriptomic, metabolomic, and gut microbiota analyses. Mechanistic involvement of the MAPK/mTOR-autophagy pathway was further validated using L-leucine as a pharmacological activator of mTOR. NGR1 markedly attenuated AILI, as reflected by reduced serum ALT/AST levels, improved hepatic histology, and increased survival in acute liver failure. NGR1 suppressed inflammatory responses by decreasing IL-1[Formula: see text], IL-6, and TNF-[Formula: see text] levels and alleviated oxidative stress by restoring GSH and SOD while reducing MPO, ROS, and MDA accumulation. Multi-omics analysis revealed significant enrichment of MAPK/mTOR signaling, autophagy, ferroptosis, and glutathione metabolism pathways. Mechanistically, NGR1 promoted autophagic flux (increased LC3-II/I, ATG5, and ATG7 with decreased p62), inhibited ferroptosis (upregulation of GPX4 and SLC7A11 with downregulation of ACSL4), and suppressed APAP-induced activation of the MAPK/mTOR pathway. Pharmacological activation of mTOR by L-leucine partly abolished the protective effects of NGR1, reversing autophagy activation and restoring inflammatory and oxidative injury. These findings collectively demonstrate that NGR1 protects against AILI by inhibiting MAPK/mTOR signaling, restoring autophagy, and suppressing ferroptosis, highlighting NGR1 as a promising therapeutic candidate for APAP-induced hepatotoxicity.
The rhubarb root and the senna leaf are two commonly used laxative herbs for functional constipation, containing dianthrones and free anthraquinones. As a free anthraquinone, emodin is a crucial constituent isolated from laxative botanicals, and it is particularly abundant in the rhubarb root, a key ingredient in the classic Chinese medicine formula MaZiRenWan (or herbal medicine CDD-2101). This study explored emodin's anti-malignancy, anti-inflammation, and underlying mechanisms. We examined emodin and other anthraquinones on human colorectal cancer cell proliferation, then used ApcMin/[Formula: see text] mice to assess effects on animal lifespan, intestinal tumor multiplicity, inflammatory cytokines, and adaptive immunity. Results showed MaZiRenWan extract inhibited HCT-116/HT-29 human cancer cells. However, two primary dianthrone sennosides, sennoside A and sennoside B, did not demonstrate such pronounced effects. Three free anthraquinones, emodin, aloe-emodin, and rhein, displayed antiproliferative effects on cancer cells, which were observed to be significantly concentration- and time-dependent, with emodin demonstrating the strongest action. Emodin was found to induce cell cycle arrest during the S-G2/M phases and trigger apoptosis. In vivo, emodin extended ApcMin/[Formula: see text] mice lifespan, reduced gut tumors, downregulated gut tissue levels of key pro-inflammatory cytokines such as IL-1α, IL-1β, IL-6, IL-17A, IL-8, G-CSF, and GM-CSF; this result was supported by the IL-8 secretion test. Emodin had no inhibitory effect on regulatory Treg cell differentiation, yet it effectively suppressed the Th1 and the Th17 cell differentiation. In conclusion, emodin prevents colorectal cancer via inhibiting cell growth, anti-inflammation, and adaptive immunity modulation, highlighting its potential in inflammation-associated colorectal cancer prevention.
Angelica sinensis (Oliv.) Diels (A. sinensis), a perennial herb with a medicinal history spanning over two millennia, is widely recognized for its effects in nourishing blood, promoting circulation, regulating menstruation, and alleviating pain. As demonstrated by over 1572 articles published since 2016, research in this field has advanced rapidly. However, the most recent comprehensive review dates back to 2016, and lacks systematic coverage of pharmacological mechanisms, structure-activity relationships (SARs), and modern applications. As a result, much of the relevant knowledge has been fragmented across disciplines. This review addresses these gaps by providing a systematic synthesis of the botany, traditional uses, phytochemistry, pharmacology, safety, and applications of A. sinensis. Over 290 chemical constituents, which can be broadly categorized into volatile oils, organic acids, polysaccharides, phenylpropanoids, and flavonoids, have been identified from A. sinensisto date. Representative bioactive compounds, such as Z-ligustilide (Z-lig), ferulic acid, and angelica coumarin A, contribute significantly to its diverse biological activities. This review offers an in-depth, mechanism-based summary of its pharmacological properties, and places a particular emphasis on the SARs of key bioactive constituents. The scope of the review is further expanded to include emerging applications in functional foods, skincare, agriculture, and animal husbandry industries. This review integrates multidisciplinary advances to establish a comprehensive and mechanistically grounded framework. This framework aims in turn to guide evidence-based utilization, foster innovative applications, and support the sustainable global development of A. sinensis as a medicinal and functional resource. However, several challenges remain in current research. These include insufficient standardization of cultivation practices, limited high-quality clinical evidence, and the lack of internationally recognized quality standards. Future research should prioritize multicenter clinical trials, the elucidation of biosynthetic pathways, and the establishment of international quality standards in order to promote the sustainable global development of A. sinensis.
Chronic atrophic gastritis (CAG) is a major precancerous lesion of gastric cancer, characterized by a high incidence rate, a protracted clinical course, and a well-documented risk of malignant transformation. Current Western medical treatments exert limited efficacy in reversing progressive gastric mucosal damage. In traditional Chinese medicine (TCM), CAG is categorized as expressing symptoms such as "stomachache" and "abdominal fullness," with the core pathogenesis defined as "spleen-stomach deficiency as the root, and qi stagnation, blood stasis, and damp-heat as the superficial manifestations." TCM confers distinct clinical advantages through therapeutic strategies which include invigorating the spleen and replenishing qi, clearing heat and resolving dampness, and promoting blood circulation to remove stasis. Ferroptosis, an iron-dependent form of regulated cell death, has been increasingly recognized as a key driver of gastric mucosal injury and disease progression in CAG, and exerts its effects via nine core pathways including iron metabolism imbalance, glutathione (GSH) depletion, lipid peroxidation (LPO), mitochondrial dysfunction, and inflammatory responses. This review systematically elaborates on the molecular mechanisms of ferroptosis in CAG pathogenesis and comprehensively summarizes recent advances in how active ingredients derived from Chinese herbal medicines (such as baicalein, curcumin, tanshinone IIA, astragaloside IV) and classic compound formulas like Sijunzi Decoction, Banxia Xiexin Decoction, Moluodan, and Weifuchun regulate ferroptosis-related signaling pathways. It further highlights the multi-target, multi-pathway characteristics of TCM in alleviating oxidative damage and promoting mucosal repair. Ultimately, this review aims to elucidate the scientific basis of TCM-mediated ferroptosis regulation in CAG management, provide novel theoretical support for clinical practice, and guide future directions for drug research and development.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder primarily characterized by β-amyloid (Aβ) deposition, Tau protein hyperphosphorylation, and chronic neuroinflammation. Current pharmacological interventions demonstrate limited therapeutic efficacy. The nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, a pivotal regulator of oxidative stress and neuroinflammation, plays a critical role in AD pathogenesis. Recent studies have revealed that traditional Chinese medicines (TCMs) and their bioactive constituents can modulate the Nrf2 signaling pathway to mitigate oxidative stress, suppress neuroinflammation, enhance Aβ clearance, and reduce Tau protein phosphorylation. By doing so, TCMs exert multi-targeted anti-AD effects. This review systematically summarizes the mechanisms and recent advances concerning the active ingredients of Nrf2 pathway-modulating TCMs, herbal medicines, and TCM formulations for the prevention and treatment of AD. Furthermore, it critically evaluates current research limitations and prospects for future research directions to provide a theoretical foundation for the development of novel anti-AD therapeutics derived from TCMs.
Liver fibrosis (LF) represents a critical pathological stage in the progression of various chronic liver diseases, and is characterized by the sustained activation of hepatic stellate cells (HSCs) and excessive deposition of extracellular matrix (ECM). These processes ultimately lead to cirrhosis and even hepatocellular carcinoma. Current therapeutic strategies for LF primarily rely on etiological interventions and supportive management. However, due to the complex pathogenesis of LF, involving multiple interconnected signaling pathways, effective and specific antifibrotic therapies remain lacking. Therefore, the development of multi-target and system-level therapeutic strategies for the treatment of LF is of considerable importance. Ginsenosides, the major bioactive components of Panax ginseng, exhibit multi-component and multi-target pharmacological properties and have shown broad potential in the prevention and treatment of liver fibrosis. Accumulating evidence indicates that several ginsenosides, including Rg1, Rb1, Rg3, Rh1, Rd, and the metabolite Compound K, exert significant antifibrotic effects across various experimental models. This review systematically summarizes the pharmacological mechanisms of ginsenosides in liver fibrosis and integrates their effects from a mechanistic perspective. Overall, ginsenosides directly target key fibrogenic processes by inhibiting HSCs activation and proliferation, promoting apoptosis, reducing ECM synthesis, and facilitating ECM degradation. In addition, they indirectly modulate fibrosis progression by regulating upstream amplifying factors such as inflammation, oxidative stress, and the immune microenvironment. Furthermore, ginsenosides also influence cell fate-related processes, including autophagy and ferroptosis, in a cell-type-dependent manner. In hepatocytes, maintaining appropriate autophagic activity and suppressing lipid peroxidation generally confers protective effects. In HSCs, by contrast, the inhibition of protective autophagy or induction of ferroptosis appears to be more relevant to antifibrotic efficacy. Although substantial experimental evidence supports the antifibrotic potential of ginsenosides, their clinical translation remains limited by low bioavailability, unclear active forms in vivo, and the lack of high-quality clinical studies. Future investigations should focus on identifying key molecular targets and underlying mechanisms through multi-omics approaches and structure-activity relationship analyses. Well-designed clinical trials should likewise be conducted to evaluate the safety and therapeutic efficacy of ginsenosides and, thereby, facilitate their clinical application in liver fibrosis.
Diabetic kidney disease (DKD) is a severe diabetic microvascular complication with a complex pathogenesis and progression driven by renal fibrosis and inflammation. As a condition, DKD imposes a heavy clinical burden. Astragaloside IV (AS-IV), the main active component of Astragalus membranaceus, exhibits renoprotective potential in DKD, but its molecular mechanisms remain unclear. This study combined network pharmacology, molecular docking, and in vivo validation in db/db mice in order to explore AS-IV's therapeutic effect on DKD and the mechanisms by which it alleviates inflammation and fibrosis. The efficacy of AS-IV was evaluated via glucose metabolism, urinary protein, hepatic/renal function, and renal histopathology using H&E, PAS, Masson staining, and transmission electron microscopy. The expressions of the MAPK pathway, fibrosis and inflammation-related molecules were detected by ELISA, Western blot, RT-qPCR, immunohistochemistry and immunofluorescence. In addition, non-targeted metabolomics was used to explore metabolic regulation. Network pharmacology identified the MAPK pathway as a core target, and molecular docking confirmed AS-IV's strong binding to MAPK1/MAPK3. In vivo, AS-IV improved glucose metabolism, reduced albuminuria, alleviated renal histological damage, inhibited ERK/JNK/p38 phosphorylation in the MAPK pathway, downregulated fibrosis-related proteins (TGF-β1, α-SMA, Collagen I/IV) and suppressed NF-κB-mediated inflammation. It furthermore ameliorated metabolic disorders, and exhibited a particular efficacy in doing so for amino acid metabolism. Collectively, AS-IV retards DKD progression by both exerting antifibrotic/anti-inflammatory effects and correcting metabolic dysregulation via inhibition of the MAPK pathway. These mechanisms provide a theoretical basis for the clinical application of AS-IV in DKD.
Icariin (ICA), an isoprenylated flavonoid glycoside extracted from the traditional Chinese herb Epimedium, is the primary bioactive constituent of that herb. ICA has been documented to have a diverse array of bioactivities which encompass anti-inflammatory and immunomodulatory effects, anti-oxidant stress resistance, anti-aging properties, antitumor activity, anti-osteoporotic effects, and reproductive function enhancement. ICA intervenes in basic processes such as cellular stress, inflammation, metabolism and death through multiple targets and pathways, and can restore the body's balance in specific pathological states. Building on these findings, this paper describes ICA's therapeutic efficacy across diverse pathologies, such as cancer, rheumatoid arthritis (RA), osteoarthritis, osteoporosis, gastrointestinal diseases, ischemic stroke, and neurodegenerative diseases, while elucidating its underlying molecular mechanisms. This study also explores new methods of preparing ICA with the goal of both expanding its therapeutic uses and supporting its clinical translation. However, the toxicological profile and clinical evidence for ICA are still not well understood, and thus, more research is needed before ICA can be confirmed as a viable treatment.
Since Ephedra Herba (ephedra) and its major alkaloid ephedrine were prohibited as dietary supplements due to their adverse effects on the cardiovascular and central nervous system (CNS), most studies have focused on their amphetamine-like effects and neurotoxicity. However, ephedra also has a long history of use in the treatment of various CNS diseases (known as "Zhong Feng" syndrome) according to two thousand years of traditional Chinese medicine (TCM) records. Pharmacokinetic reports have also demonstrated that alkaloids of ephedra can quickly penetrate the blood-brain barrier (BBB) once absorbed into the blood and there are multiple alkaloids derived from ephedra which have been identified as natural sympathomimetic drugs. These drugs are capable of interfering with several types of neurotransmitter, and have an especially potent effect on monoamine neurotransmitters. The effects of ephedra on CNS therefore remain both contradictory and confusing. In this review, we summarized the available evidence of pharmacology and toxicology of ephedra and ephedrine on CNS, and aimed to clarify their effects. Given the unmet need for more efficient treatments of neurological disorders, ephedra is potentially valuable herbal medicine which may provide a promising avenue for development of treatments and encourage further drug research and development (R&D).
Curcumin, a bioactive compound and vibrant yellow pigment extracted from the rhizome of Curcuma longa, has a well-established safety profile and demonstrates defined pharmacological activities. These activities include regulating glucose and lipid metabolism, exerting anti-oxidant effects, and modulating autophagy. However, its pharmacokinetic limitations-notably low oral bioavailability and insufficient blood concentration-present a dichotomy with its significant biological effects. Research indicates that curcumin undergoes rapid and extensive metabolic transformation in vivo, which suggests that its pharmacological actions may be partially mediated by metabolites. Notably, curcumin metabolites exhibit activity comparable to, or even exceeding, the therapeutic potential of the parent compound in models of glucose and lipid metabolism disorders. Through a systematic review of curcumin's metabolic pathways and the targets of its metabolites, we identified several key conclusions. First, the beneficial effects of curcumin on glucose and lipid metabolism are closely linked to its reduced metabolites dihydrocurcumin, tetrahydrocurcumin, and hexahydrocurcumin. Second, the parent compound curcumin and its metabolites exhibit overlapping actions on core signaling pathways, such as PPARα, NF-κB, and PI3K-AKT, which confirms metabolites as significant contributors to the overall efficacy. Third, preclinical research focusing on these reduced metabolites offers promising new directions for combination therapies targeting glucose and lipid metabolism disorders and their complications. Building upon these conclusions, this paper further synthesizes the structure-activity relationships of the principal reduced metabolite-tetrahydrocurcumin, which is characterized by its high abundance among metabolites and concentrated research focus on its modification, and aims to provide a theoretical foundation for structure optimization and drug development based on metabolites.
